The use of 2-phenyl-2-methyl propanoic acid derivatives as intermediates in the preparation of fexofenadine and salts thereof is known, for example, from U.S. Pat. No. 4,254,129 and from U.S. Pat. No. 5,750,703. A key point in the preparation of fexofenadine according to known methods is the use of 2-[4-(4-chloro-butyryl)phenyl]-2-methylpropionic acid (CKA) and of 2-[(4-cyclopropyl-carbonyl)-phenyl]-2-methylpropionic acid (CPKA), in the form of substantially pure regioisomers.
According to U.S. Pat. No. 5,750,703, such intermediates are obtained through a process comprising:
a) reacting a compound of formula (I)

with a compound of formula (II)Cl—(CH2)3—COX   (II)
wherein X is a halogen atom, in particular chlorine, to obtain a first mixture of isomers having formula (III)

b) hydrolyzing a first mixture of isomers of formula (III) to obtain a second mixture of isomers of formula (IV)

c) purifying said second mixture by fractional crystallization to obtain a substantially pure (para) isomer of formula (V), and finally

d) halogenating said substantially pure para-isomer of formula (V) to obtain, for example, 2-[4-(4-chloro-butyryl)phenyl]-2-methyl propionic acid of formula (VI)

According to the same patent, 2-[4-(4-chloro-butyryl)phenyl]-2-methyl propionic acid of formula (VI) (CKA) or 2-[(4-cyclopropyl-carbonyl)-phenyl]-2-methylpropionic acid of formula (V) (CPKA), or an alkyl ester thereof, is then reacted with a piperidine compound of formula (VII)

to obtain a ketone compound of formula (VIII) or a alkyl ester thereof,

from said compound of formula (VIII), if the case after hydrolysis of the ester group, by reduction of the carbonyl group, fexofenadine of formula (IX) is obtained

Such process envisages some considerable drawbacks. For example, the substantially pure para regioisomer of formula (V) can be obtained by fractional crystallization from a great variety of salts thereof, for example from alkali salts, for example of sodium or potassium, or more preferably from an ammonium salt of formula R7R8R9N, wherein R7, R8 and R9 are H, or straight or branched optionally substituted C1-C6 alkyl, or a substituted phenyl. Said salt can also be a cinchonidine, quinine, quinidine, quinuclidine, brucine, thebaine or cinchonine salt. The cinchonidine salt is intended as preferred. The use of cinchonidine is illustrated in experimental example 2, which describes the purification of said second mixture by fractional crystallization to isolate a substantially pure para isomer of formula (V). Cause of the unfavorable ratio among the isomers, the purification results in a greater than 50% loss of material, experimental example 2 in fact shows a 33% yield. Moreover, since cinchonidine costs 10 times more than the commercial cost of substantially pure para isomer of formula (V), this procedure is expensive and deeply impacts on the cost of the final medicine.
The Indian patent application IN 1225DEL2006 partly solves the problem of obtaining 2-[4-(4-chloro-butyryl)phenyl]-2-methyl propionic acid of formula (VI), reported above, as substantially pure para-isomer, by a process comprising the purification of a mixture of meta and para isomers of a compound of formula (X)

to remove the meta isomer, for example by slurry or by selective crystallization using an organic solvent, for example cyclohexane, hexane, heptane, isopropyl ether, preferably cyclohexane.
Even if the mentioned method is efficient, it is actually effective and usable only when the ratio between the meta and the para isomer is lower than 10/90, as reported in the experimental examples of the patent application.
The inventors of the present invention, when repeating the method disclosed in IN 1225DEL2006 and using regioisomeric mixtures of a compound of formula (X) with a higher content of meta isomer, that is mixtures wherein the ratio between the meta isomer and the para isomer is comprised between 15/85 and 50/50, obtained neither the formation of a precipitate of a compound of formula (VI), nor the purification of the mixture of meta and para regioisomers of the compound of formula (X).
Moreover, according to IN 1225DEL2006, said mixture wherein the ratio between the meta and the para isomer is lower than 10/90, is obtained through a long and tiresome method, comprising condensing a compound of formula (II), as defined above, with 1-acetoxy-2-methyl-2-phenylpropane of formula (XI)

to obtain a compound of formula (XII) containing more than 80% of para isomer,

acid hydrolysis of a compound of formula (XII) to obtain a compound of formula (XIII), and

oxidation of said compound of formula (XIII) to obtain an acid of formula (X).
Even in this case, the cost of this process deeply impacts on the cost of the final medicine.
There is therefore the need of an alternative process, that can be validly industrially applicable for the preparation of 2-[4-(4-chloro-butyryl)phenyl]-2-methylproprionic acid (CKA) and of 4-(cyclopropyl-oxo-methyl)-α,α-dimethtlphenylacetic acid (CPKA), as substantially pure para regioisomers.
The inventors of the present invention have found that the preparation on industrial scale of said acids as substantially pure para regioisomers can be carried out by a purification process comprising their isolation by selective crystallization of an ammonium salt thereof.